Environmental cues associated with alcohol are more likely to precipitate relapse if experienced in an environmental context associated with past alcohol consumption, as opposed to a context in which alcohol was never consumed. Here we will study contextual modulation of responding to alcohol-conditioned cues in behavioral models of relapse in which rats are trained in a distinctive context to discriminate between one auditory stimulus paired with alcohol (CS+) and a second (CS-) that is never paired with alcohol; conditioned responding is measured as increased entries into the alcohol delivery port during the CS+ relative to the CS-. After extinction of responding in a different context, placement back into the original alcohol training environment enhances CS+-driven alcohol-seeking behavior ('relapse'). Using this paradigm, we propose to investigate the neural circuitry underlying the modulation of cue-induced alcohol-seeking by context using techniques of site-specific microinjections and in vivo electrophysiology. Specifically, we hypothesize that reinstatement of responding to a discrete alcohol-predictive cue requires excitatory projections from the basolateral amygdala (BLA) to the nucleus accumbens core (NACc), whereas the augmentation of this behavior by an alcohol context requires efferents from the ventral hippocampus (vHipp) to the BLA. In Aim 1 we will examine the independent roles of the BLA and NACc, as well as the BLA-NACc pathway, in cue- induced alcohol-seeking. Aim 2 will determine if contextual control over alcohol-seeking occurs via vHipp efferents to the BLA. Aim 3 will further define the neural mechanisms involved by examining neuronal responses to alcohol-predictive cues in the BLA, their modulation by context. Collectively, these studies will refine our understanding of the neural underpinnings of contextual modulation of alcohol-seeking, and may give rise to new therapeutic treatments for relapse in alcoholism. PUBLIC HEALTH RELEVANCE: Exposure to stimuli that have been associated with past alcohol use is thought to contribute to propensity to relapse in human alcoholics. The environment in which alcohol was habitually consumed may be a particularly potent relapse cue. The studies in this proposal are designed to reveal neurobiological mechanisms that underlie the ability of alcohol-associated contexts to trigger relapse.